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increase in XBP1 splicing (
Thuerauf et al., 2006
). The majority of these
and other in vitro findings have been replicated in animal models and clini-
cal studies under various conditions (
Thuerauf et al., 2006
;
Severino et al.,
2007
;
Toko et al., 2010
;
Perman et al., 2011
). Studies in wild-type animals
showed that ATF6 transcription was increased 6 h after ischemia (
Perman
et al., 2011
). Alternatively,
Thuerauf et al. (2006)
found that BiP/GRP78
levels were elevated even 4 days after ischemic injury in cardiomyocytes.
Under ischemic conditions, the lack of oxygen and nutrients poses a
serious threat to cardiomyocyte viability. At the mechanistic level, insuf-
ficient ATP impairs disulfide bond formation and fosters inappropriate
calcium handling, both processes that have been suggested to trigger UPR
in heart. Disulfide bond formation is critical for folding of secreted pro-
teins, and the ER-resident chaperones involved, Ero1, PDI and ERp57,
require oxygen as a final electron acceptor for the serial redox reactions
required for this process (
Anelli and Sitia, 2008
). Correct glycosylation of
membrane proteins is required for both trafficking and proper biological
function. Recent studies suggest that insufficient ATP availability affects
UDP-sugar formation and triggers ER stress by interfering with glycosyl-
ation. The sudden drop in nutrient flux during ischemic heart disease leads
rapidly to energy and ATP shortage. Additionally, high calcium levels in
the ER are required for chaperones such as BiP/GRP78 to aid in protein
folding. The pathological changes in ER calcium levels during ischemia
due to decreased SERCA2 activity can effectively stimulate ER stress (
Liu
et al., 2011
).
Although activation of the UPR in ischemic heart disease is well
established, the precise biological role of the UPR in this process remains
unclear, since available evidence indicates that activation of the UPR can
be either beneficial or detrimental. Most studies have attempted to address
this question by evaluating activity of proapoptotic branches of the UPR
following genetic or pharmacological manipulation. For instance, studies
withVLDL-deficient rats established that protection of the heart from isch-
emic insult correlated with a decrease in caspase activity and apoptotic cell
death (
Perman et al., 2011
). Likewise, this correlation was evident in a rat
ischemia model where BiP/GRP78, CHOP and caspase-12 were evaluated
(
Song et al., 2011
). These studies suggest that ER stress during ischemia
stimulates cell death, and inhibition of ER stress may ameliorate cardiomy-
opathy. However, evidence for a beneficial role of the UPR in this process
also exists (
Thuerauf et al., 2006
), since in vitro and in vivo approaches
using gain- and loss-of function approaches showed that the UPR protects
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